Professor Carl Smythe
Professor of Cell Biology
Director: Faculty of Science Mass Spectrometry Centre
Department of Biomedical Science
The University of Sheffield
Sheffield S10 2TN
Room: E03a Florey building
Telephone: +44 (0) 114 222 4643
Brief career history
Cellular surveillance systems and their role in healthy aging
Research in our laboratory uses molecular cell biology approaches to understand quality control or surveillance mechanisms that operate in cells to ensure fidelity of function, the consequences when they fail, and how they may be exploited to ameliorate disease. Examples include the replication checkpoint, which operates to ensure that cells experiencing replication stress, can evoke appropriate DNA damage responses, reschedule cell cycle events, or initiate apoptosis, and quality control systems regulating processes involving RNA homeostasis, such as nonsense-mediated decay (NMD), histone mRNA decay (HD), and telomere stability.
We utilise a variety of disease cell models in mechanistic studies and utilise whole genome and new chemical entity (NCE) screening together with mass spectrometry and imaging techniques, coupled with in vitro assays, to synergistically probe both biological and NCE function.
Our chemical biology work focuses on exploring the use of ruthenium co-ordination complexes to explore novel chemical space affecting pathways of interest, as well as novel indole polycyclic derivatives that block NMD.
Our focus is to identify potential new therapeutic targets in relevant disease models, and our work on the replication checkpoint has identified a number of proteins and /or pathways which are of interest.
A key focus concerns the functional characterisation of the DNA /RNA helicase Upf1 which acts pleiotropically to regulate NMD, HD and telomere integrity. We have identified a novel NMD inhibitor which, importantly, does not affect histone mRNA regulation or telomere integrity. We aim to utilise our expertise in genomic integrity and mass spectrometry to identify the target of this inhibitor as a potential therapeutic strategy for the treatment of nonsense mutation-associated disease.
Undergraduate and postgraduate taught modules
- Gotham VJB, Hobbs MC, Burgin R, Turton D, Smythe C & Coldham I (2016) Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay. Org. Biomol. Chem., 14(5), 1559-1563. View this article in WRRO
- Block KI, Gyllenhaal C, Lowe L, Amedei A, Amin ARMR, Amin A, Aquilano K, Arbiser J, Arreola A, Arzumanyan A , Ashraf SS et al (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Seminars in Cancer Biology, 35, S276-S304. View this article in WRRO
- Ramu V, Gill M, Jarman P, Turton D, Thomas J, Das A & Smythe CG (2015) A Cytostatic Ruthenium(II)–Platinum(II) Bis(terpyridyl) Anticancer Complex That Blocks Entry into S Phase by Up-regulating p27KIP1. Chemistry - A European Journal, 21(25), 9185-9197. View this article in WRRO
- Baggaley E, Gill MR, Green NH, Turton D, Sazanovich IV, Botchway SW, Smythe C, Haycock JW, Weinstein JA & Thomas JA (2014) Dinuclear ruthenium(II) complexes as two-photon, time-resolved emission microscopy probes for cellular DNA.. Angew Chem Int Ed Engl, 53(13), 3367-3371. View this article in WRRO
- Gill MR, Garcia-Lara J, Foster SJ, Smythe C, Battaglia G & Thomas JA (2009) A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells. NAT CHEM, 1(8), 662-667.
- Müller B, Blackburn J, Feijoo C, Zhao X & Smythe C (2007) DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication. Journal of Cell Biology, 179(7), 1385-1398. View this article in WRRO
- Bolderson E, Scorah J, Helleday T, Smythe C & Meuth M (2004) ATM is required for the cellular response to thymidine induced replication fork stress.. Hum Mol Genet, 13(23), 2937-2945.
- Feijoo C, Hall-Jackson C, Wu R, Jenkins D, Leitch J, Gilbert DM & Smythe C (2001) Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. JOURNAL OF CELL BIOLOGY, 154(5), 913-923. View this article in WRRO
- Novodvorsky P, Watson O, Gray C, Wilkinson RN, Reeve S, Smythe C, Beniston R, Plant K, Maguire R, M. K. Rothman A , Elworthy S et al () klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes. PLOS ONE, 10(10), e0141611-e0141611. View this article in WRRO